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Current Opinion in Lipidology Apr 2001A site-specific post-transcriptional cytidine to uridine deamination reaction is responsible for the production of apolipoprotein B48 in the mammalian small intestine.... (Review)
Review
A site-specific post-transcriptional cytidine to uridine deamination reaction is responsible for the production of apolipoprotein B48 in the mammalian small intestine. The molecular machinery responsible for apolipoprotein B RNA editing consists of apobec-1, an RNA-specific cytidine deaminase that functions in conjunction with a recently identified protein referred to as ACF/ASP. These proteins together represent the minimal editing enzyme, although other proteins may associate with the enzyme complex. Apobec-1 is a member of a supergene family of cytidine deaminases, with several homologs recently identified in the human genome. ACF/ASP is novel, and emerging information reveals interesting clues to its role in the apolipoprotein B RNA editing enzyme complex.
Topics: Apolipoproteins B; Base Pairing; Base Sequence; Cytidine; Lipoproteins; Molecular Sequence Data; RNA Editing; RNA, Messenger; Uridine
PubMed: 11264987
DOI: 10.1097/00041433-200104000-00009 -
The Journal of Clinical Investigation May 1999Apo B-100 of LDL can bind to both the LDL receptor and megalin, but the molecular interactions of apo B-100 with these 2 receptors are not completely understood....
Apo B-100 of LDL can bind to both the LDL receptor and megalin, but the molecular interactions of apo B-100 with these 2 receptors are not completely understood. Naturally occurring mutant forms of apo B may be a source of valuable information on these interactions. Apo B-70.5 is uniquely useful because it contains the NH2-terminal portion of apo B-100, that includes only one of the two putative LDL receptor-binding sites (site A). The lipoprotein containing apo B-70. 5 (Lp B-70.5) was purified from apo B-100/apo B-70.5 heterozygotes by sequential ultracentrifugation combined with immunoaffinity chromatography. Cell culture experiments, ligand blot analysis, and in vivo studies all consistently showed that Lp B-70.5 is not recognized by the LDL receptor. The kidney was identified as a major organ in catabolism of Lp B-70.5 in New Zealand white rabbits. Autoradiographic analysis revealed that renal proximal tubular cells selectively removed Lp B-70.5. On ligand blotting of renal cortical membranes, Lp B-70.5 bound only to megalin. The ability of megalin to mediate cellular endocytosis of Lp B-70.5 was confirmed using retinoic acid/dibutyryl cAMP-treated F9 cells. This study suggests that the putative LDL receptor-binding site A on apo B-100 might not by itself be a functional binding domain and that the apo B-binding sites recognized by the LDL receptor and by megalin may be different. Moreover, megalin may play an important role in renal catabolism of apo B truncations, including apo B-70.5.
Topics: Animals; Apolipoprotein B-100; Apolipoproteins B; Autoradiography; Binding Sites; Binding, Competitive; Cell Line; Heymann Nephritis Antigenic Complex; Humans; Kidney; Membrane Glycoproteins; Peptide Fragments; Rabbits; Receptors, LDL; Transfection
PubMed: 10330424
DOI: 10.1172/JCI4921 -
The Journal of Biological Chemistry Jun 1995Translocation of apolipoprotein (apo) B across the endoplasmic reticulum membrane is a likely site for regulation of secretion of very low density lipoproteins from the...
Translocation of apolipoprotein (apo) B across the endoplasmic reticulum membrane is a likely site for regulation of secretion of very low density lipoproteins from the liver. When primary rat hepatocytes are enriched with the phospholipid phosphatidylmonomethylethanolamine, the secretion of apoB, but not other proteins such as apoprotein A1 and albumin, is disrupted (Vance, J. E. (1991) J. Lipid Res. 32, 1971-1982). Moreover, less apoB enters the microsomal lumen and the intracellular degradation of apoB is increased (Rusiñol, A. E., Chan, E. Y. W., and Vance, J. E. (1993a) J. Biol. Chem. 268, 25168-25175). In the present study we have used McArdle 7777 rat hepatoma cells stably transfected with carboxyl-terminal-truncated variants of human apoB100 and have demonstrated that the reduction in apoB secretion induced by phosphatidylmonomethylethanolamine is not a function of assembly of the apoB into a buoyant lipoprotein particle. In addition, inhibition of the intracellular degradation of the apoproteins B does not restore apoB secretion, suggesting that the effect of phosphatidylmonomethylethanolamine enrichment on apoB degradation is secondary to the effect on translocation of the protein into the endoplasmic reticulum lumen. Furthermore, supplementation of the culture medium with oleic acid does not increase apoB secretion, reduce the intracellular degradation of apoB or reverse the effects of phosphatidylmonomethylethanolamine enrichment on these processes. Our data support the hypothesis that translocation of apoB protein across the endoplasmic reticulum membrane, regardless of the association of the apoB with neutral lipids, may be a key regulatory step in very low density lipoprotein secretion.
Topics: Animals; Apolipoproteins B; Biological Transport; Endoplasmic Reticulum; Ethanolamines; Humans; Hydrolysis; Intracellular Membranes; Microsomes, Liver; Oleic Acid; Oleic Acids; Rats; Trypsin; Tumor Cells, Cultured
PubMed: 7768932
DOI: 10.1074/jbc.270.22.13318 -
Journal of Clinical Lipidology 2016
Topics: Apolipoprotein B-100; Apolipoproteins B; Humans; Hyperlipoproteinemia Type II; Mutation
PubMed: 27578140
DOI: 10.1016/j.jacl.2016.04.007 -
Zhonghua Xin Xue Guan Bing Za Zhi Jun 2006
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Alimentary Pharmacology & Therapeutics Jul 2023Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby...
BACKGROUND
Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis.
AIM
To examine the effects of missense variants in MTTP on hepatic and circulating lipids.
METHODS
We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444).
RESULTS
We analysed 24 missense variants in MTTP in PMBB for association with biopsy-proven hepatic steatosis and found that an isoleucine 128 to threonine variant (I128T: rs3816873-A, frequency 26%) was associated with reduced steatosis (p < 0.001). PMBB subjects with imaging-proven steatosis also revealed significantly fewer carriers of MTTP I128T compared to controls. Analysis in UKB also showed that MTTP I128T was associated with reduced risk of hepatic steatosis. Unexpectedly, MTTP I128T was found to be associated with reduced plasma levels of LDL-cholesterol and apoB (all p < 0.001). Functional studies indicated that MTTP I128T is neither a classic loss nor gain of function allele.
CONCLUSIONS
MTTP I128T is associated with reduced hepatic steatosis as well as reduced plasma lipids and apoB. This paradoxical profile is not consistent with a simple gain or loss of function in MTP activity and suggests a more complex effect on MTP function. Further investigation of MTTP I128T will provide insight into the structure-function of MTP and potentially new approaches to modulate MTP activity that could both reduce hepatic and circulating lipids.
Topics: Humans; Carrier Proteins; Fatty Liver; Apolipoproteins B
PubMed: 37248657
DOI: 10.1111/apt.17566 -
Drug Design, Development and Therapy 2023Traditional Chinese medicine (TCM) with single or compound materials is an effective cure for liver fibrosis. Hepatic stellate cells (HSCs) play a key role in liver...
BACKGROUND
Traditional Chinese medicine (TCM) with single or compound materials is an effective cure for liver fibrosis. Hepatic stellate cells (HSCs) play a key role in liver fibrosis pathology and have become a novel drug target for this condition.
METHODS
CCK-8 assay was used to determine the cytotoxicity of four components, SYPA, HSYPA, Apigenin, and Luteolin, from Deduhonghua-7 powder on HSC-T6 cells. Transforming Growth Factor β 1 (TGFβ1)-induced fibrotic cell model and CCI-induced fibrotic rat model were constructed, the expression of fibrosis-related genes, the pathological changes and serum biochemical markers were evaluated. Proteomic analysis was performed to determine the mechanism by which luteolin attenuated liver fibrosis, which were further confirmed by Western blot.
RESULTS
Luteolin attenuates liver fibrosis in HSC-T6 cells and luteolin decreases the liver fibrosis index level in vivo. A total of 5000 differentially expressed proteins (DEPs) were obtained using proteomic analysis. KEGG analysis found that DEPs were concentrated in various metabolic pathways, including DNA replication and repair and lysosomal signaling. GO analysis showed that molecular functions included the activity and binding of various enzymes, related cellular components included the extracellular space, lysosomal lumen, mitochondrial matrix, and nucleus, and biological processes included collagen organization and biosynthesis and the positive regulation of cell migration. Western blot results showed that CCR1, CD59, and NAGA were downregulated in TGFβ1 treatment, while upregulated both in Lut2 and Lut10 treatment. Meanwhile, eight proteins, ITIH3, MKI67, KIF23, DNMT1, P4HA3, CCDC80, APOB, FBLN2, that were upregulated in TGFβ1 treatment, while downregulated both in Lut2 and Lut10 treatment.
CONCLUSION
Luteolin was shown to have a strong protective effect on liver fibrosis. CCR1, CD59, and NAGA may promote liver fibrosis while ITIH3, MKI67, KIF23, DNMT1, P4HA3, CCDC80, APOB, and FBLN2 may facilitate protection against fibrosis.
Topics: Rats; Animals; Hepatic Stellate Cells; Luteolin; Proteomics; Cell Line; Liver Cirrhosis; Apolipoproteins B; Liver
PubMed: 37360572
DOI: 10.2147/DDDT.S402864 -
Progress in Lipid Research 1991
Review
Topics: Apolipoproteins A; Apolipoproteins B; Cardiovascular Diseases; Female; Humans; Immunologic Techniques; Lipoproteins; Male
PubMed: 1823945
DOI: 10.1016/0163-7827(91)90024-y -
Annual Review of Nutrition 2000Apolipoprotein (apo)B circulates in two distinct forms, apoB100 and apoB48. Human liver secretes apoB100, the product of a large mRNA encoding 4536 residues. The small... (Review)
Review
Apolipoprotein (apo)B circulates in two distinct forms, apoB100 and apoB48. Human liver secretes apoB100, the product of a large mRNA encoding 4536 residues. The small intestine of all mammals secretes apoB48, which arises following C-to-U deamination of a single cytidine base in the nuclear apoB transcript, introducing a translational stop codon. This process, referred to as apoB RNA editing, operates through a multicomponent enzyme complex that contains a single catalytic subunit, apobec-1, in addition to other protein factors that have yet to be cloned. ApoB RNA editing also exhibits stringent cis-acting requirements that include both structural and sequence-specific elements-specifically efficiency elements that flank the minimal cassette, an AU-rich RNA context, and an 11-nucleotide mooring sequence-located in proximity to a suitably positioned (usually upstream) cytidine. C-to-U RNA editing may become unconstrained under circumstances where apobec-1 is overexpressed, in which case multiple cytidines in apoB RNA, as well as in other transcripts, undergo C-to-U editing. ApoB RNA editing is eliminated following targeting of apobec-1, establishing that there is no genetic redundancy in this function. Under physiological circumstances, apoB RNA editing exhibits developmental, hormonal, and nutritional regulation, in some cases related to transcriptional regulation of apobec-1 mRNA. ApoB and the microsomal triglyceride transfer protein (MTP) are essential for the assembly and secretion of apoB-containing lipoproteins. MTP functions by transferring lipid to apoB during its translation and by transporting triglycerides into the endoplasmic reticulum to form apoB-free lipid droplets. These droplets fuse with nascent apoB-containing particles to form mature, very low-density lipoproteins or chylomicrons. In cultured hepatic cells, lipid availability dictates the rate of apoB production. Unlipidated or underlipidated forms of apoB are subjected to presecretory degradation, a process mediated by retrograde transport from the lumen of the endoplasmic reticulum to the cytosol, coupled with multiubquitination and proteasomal degradation. Although control of lipid secretion in vivo is primarily achieved at the level of lipoprotein particle size, regulation of apoB production by presecretory degradation may be relevant in some dyslipidemic states.
Topics: Animals; Apolipoproteins B; Base Sequence; Chylomicrons; Gene Expression Regulation; Humans; Intestine, Small; Lipid Metabolism; Lipids; Liver; RNA Editing; RNA Processing, Post-Transcriptional; RNA, Messenger
PubMed: 10940331
DOI: 10.1146/annurev.nutr.20.1.169 -
Biochemical and Biophysical Research... May 1986Human hepatocarcinoma Hep G2 cells were grown in culture medium containing [45Ca2+]. The secreted lipoproteins of d less than 1.063 g/ml and d 1.063-1.21 g/ml were...
Human hepatocarcinoma Hep G2 cells were grown in culture medium containing [45Ca2+]. The secreted lipoproteins of d less than 1.063 g/ml and d 1.063-1.21 g/ml were isolated from the culture media and analyzed by 3.3% and 7% SDS-polyacrylamide gel electrophoresis. Radioactivity profiles of [45Ca] from the gels showed that the peak of radioactivity corresponded to the apolipoprotein B band. The molar ratio of the incorporated [45Ca2+] and apolipoprotein B was close to unity. No radioactivity was found associated with any other secreted apolipoproteins. To confirm these findings, apolipoprotein B-containing lipoproteins were precipitated with anti-apolipoprotein B and high density lipoproteins were precipitated with anti-apolipoprotein A-I. Only the former precipitate was radioactive. These results suggest that apolipoprotein B is a calcium binding protein.
Topics: Animals; Apolipoprotein A-I; Apolipoproteins A; Apolipoproteins B; Calcium; Calcium-Binding Proteins; Cell Line; Humans; Liver Neoplasms, Experimental
PubMed: 3087360
DOI: 10.1016/0006-291x(86)91237-4